Donanemab, an Anti-Amyloid Beta Antibody, Reduces Cognitive Decline and Clears Both Amyloid Beta Plaque and Tau Neurofibrillary Tangles 

A symposium at the Clinical Trials in Alzheimer Disease meeting, held in Boston, MA Nov 9-12, 2021, reviewed clinical trials of donanemab (Eli Lilly, Indianapolis, Indiana.) Donanemab is an anti-amyloid antibody being submitted on a rolling basis to the Food and Drug Administration (FDA) for accelerated approval for treatment of Alzheimer disease (AD). 

In the phase 2 TRAILBLAZER-AD study (NCT03367403), treatment with donanemab vs placebo rapidly cleared amyloid beta (A) plaques and slowed clinical decline by approximately 32% in individuals with early symptomatic Alzheimer disease (AD). In this trial and in the ongoing TRAILBLAZER 2 trial (NCT04437511), A levels are measured with amyloid and tau positron emission tomography (PET). Levels of phosphorylated tau (Ptau)were also measured in plasma. 

Treatment with donanemab reduced Ptau217 by 24% from baseline, and this effect began to be seen as early as 12 weeks after treatment. In contrast, with placebo, Ptau217 increased by 6% from baseline to the end of the 76-week study. Changes in Ptau217 levels correlated positively with reductions in A plaque and tau neurofibrillary tangles (NFTs), the 2 pathologic hallmarks of AD. Investigators for the study suggest that Ptau217 could be a plasma biomarker for treatment efficacy, and this continues to be studied in additional trials. 

The design of the currently enrolling phase 3 TRAILBLAZER-3 study (NCT05026866) was also presented. Planned enrollment is 3,300 participants who have signs of AD pathology, as evidenced by Ptau217 plasma levels, but who do not have cognitive impairments including mild cognitive impairment or other clinical symptoms. The goal is to determine whether donanemab can prevent or delay progression to clinically symptomatic AD, and the event-based outcome measure is time to clinical progression. Participants will be followed until 434 have had an increase at 2 consecutive visits on the Clinical Dementia Rating Global Score (CDR-GS). The trial will use a decentralized approach with visits conducted remotely in whole or in part with a goal of increasing participation from historically underrepresented groups.